Histone deacetylases (HDACs) are involved in the regulation of DNA expression. They are implicated in many diseases, such as neurological disorders (e.g., Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and dementia), cancer, and chronic obstructive pulmonary disorder (COPD). HDACs are also involved in immune responses to infectious disease.
HDAC, inhibitors are histone-modifying enzymes involved in the removal of acetyl groups from lysine residues and the remodeling of chromatin structure, which has a key role in the epigenetic regulation of gene expression (Graff, J., and Tsai, L. H. (2013). Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 14, 97-111; Shahbazian, M. D., and Grunstein, M. (2007). Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem 76, 75-100). Because of their dramatic impact on gene regulation, HDAC inhibitors are promising targets in drug development for many diseases such as cancers and neurodegenerative disorders (Bolden, J. E., Peart, M. J., and Johnstone, R. W. (2006). Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5, 769-784; Chuang, D. M., Leng, Y., Marinova, Z., Kim, H. J., and Chiu, C. T. (2009). Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 32, 591-601; Kazantsev, A. G., and Thompson, L. M. (2008). Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov 7, 854-868; Minucci, S., and Pelicci, P. G. (2006). Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6, 38-51). Indeed, several classes of HDAC inhibitors administered orally have been found to attenuate the progression of a repertoire of cancers and neurodegenerative diseases including Alzheimer's disease and Huntington's disease (Chuang, D. M., Leng, Y., Marinova., Z., Kim, H. J., and Chiu, C. T. (2009). Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 32, 591-601).
In particular, neurodegeneration and neuronal senescence in mammals is often associated with the accumulation of heterochromatin, which may lead to down-regulation of neuronal gene expression involved in learning and memory. There are challenges to identify effective therapeutics for neurological conditions, for example due to a lack of protein targets or the difficulty identifying drugs that can cross the blood-brain barrier. The epigenetic machinery, such as HDAC, involved in disease processes is one avenue that may have great effects in developing treatments. One method of modulating HDAC is through the use of HDAC inhibitors.
Thus, methods of identifying new classes of volatile histone deacetylase inhibitors, and methods of using such histone deacetylase inhibitors for the prophylaxis and treatment of diseases and disorders, are needed in the art.